Medical devices for fluid delivery and methods of use and manufacture

ABSTRACT

Medical devices and methods for delivering fluid. The medical devices include one or more needles for delivering fluid. The methods may optionally include expanding an expandable member such as an inflatable member to expand an expandable scaffold outward toward a lumen wall. The methods may include delivering a first fluid out of one or more needles, and delivering a secondary fluid (which may be the same type of fluid as the first fluid, or a different type of fluid) from the device without delivering the secondary fluid through a needle.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a bypass continuation of International ApplicationPCT/US2022/017068, filed Feb. 18, 2022, which claims the benefit ofpriority to U.S. Prov. App. No. 63/152,420, filed Feb. 23, 2021, theentire disclosures of which is incorporated by reference herein for allpurposes.

This application incorporates by reference herein for all purposes theentire disclosure of U.S. Pat. No. 11,071,847, issued Jul. 27, 2021.

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

FIELD

Intravascular (e.g., perivascular or adventitial) delivery of agents forthe treatment of peripheral artery disease.

BACKGROUND

It is estimated that more than 20 million patients have peripheralartery disease (PAD), which can progress to critical limb ischemia(CLI), the most serious form of PAD.

Local luminal drug delivery with drug coated balloons (DCBs) and drugeluting stents (DES) have demonstrated some improvement in patency ratesfollowing above-the-knee revascularization, yet DCBs and DES havestruggled to demonstrate improved patency following below-the-knee (BTK)interventions. A variety of causes for inconsistent results from DCB forthe treatment of BTK PAD have been proposed by leaders in the field,such as: the high prevalence of intimal and medical calcification in BTKlesions that creates a physical barrier to effective drug penetrationinto the adventitia of the vessel, resulting in the inability toeffectively inhibit a key contributor to the restenosis cascade; limiteddosage from smaller drug-coated balloons; and wash-off of the drug fromthe balloon surface during device delivery to the target lesion site.

To address these limitations, recent attempts have been made at treatingBTK PAD and CLI with an infusion catheter following primary angioplastyand/or primary atherectomy intervention. Yet inherent limitations remainwith current infusion catheter systems, inclusive but not limited to,the use of a single infusion channel, single needle, and/or a fixedlength single needle approach. Due to the limitations of existinginfusion catheter systems, treating longer lesions can be timeconsuming, inherently user dependent, and inconsistent in coverage ofthe delivered therapy, both circumferentially and longitudinally alongthe length of the lesion.

Approaches are needed that address one or more of the deficiencies setforth above.

Additionally, it may be desirable to deliver one or more fluids todifferent depths of the vessel wall.

SUMMARY OF THE DISCLOSURE

This disclosure is related to intravascular delivery of agents for thetreatment of peripheral artery disease.

One aspect of the disclosure is an intravascular apparatus adapted fordelivery of a fluid.

In this aspect, the apparatus may comprise an inflatable balloon havingan inflated cylindrical configuration.

In this aspect, the apparatus may comprise an expandable infusionscaffold comprising one or more primary spines disposed about an outercylindrical surface of the inflatable balloon.

In this aspect, the one or more primary spines may comprise a pluralityof primary radial openings therethrough, each of the plurality ofprimary radial openings associated with a needle that has a deliveryconfiguration within a primary spine lumen of the primary spine in whicha distal tip of the needle is radially constrained by the primary spine,and a deployed configuration in which the needle extends radiallyoutward from the associated primary opening after the needle is advancedaxially relative to the primary spine to facilitate delivery of aprimary agent from the needle.

In this aspect, one or more primary spines may further comprise one ormore secondary openings therethrough that are not associated with aneedle and are not adapted to deploy a needle therefrom, and wherein theone or more secondary openings are in communication with the primaryspine lumen to facilitate delivery of a secondary agent through theprimary spine lumen and out of the one or more secondary openings.

In this aspect, the inflatable balloon may have a tapered proximal endand a tapered distal end, and wherein the cylindrical configuration ofthe balloon is in between the tapered proximal and distal ends. One ormore primary spines may also be disposed about the optionally taperedproximal end.

In this aspect, one or more secondary openings may be circumferentiallyaligned with the plurality of primary openings.

In this aspect, one or more secondary openings in the associated primaryspine may be circumferentially offset from the plurality of primaryopenings.

In this aspect, a first subset of secondary openings may becircumferentially aligned with the plurality of primary openings, and asecond subset of secondary openings may be circumferentially offset fromthe plurality of primary openings.

In this aspect, one or more secondary openings may be axially offsetfrom the plurality of primary openings.

In this aspect, one or more secondary openings may be axially alignedwith and circumferentially offset from one of the plurality of primaryopenings.

In this aspect, the primary radial openings may also be in communicationwith the primary spine lumen to facilitate delivery of a secondary agentout of the one or more primary openings.

In this aspect, each of the plurality of primary openings may be largerthan one or more secondary openings.

In this aspect, one or more secondary openings may be the same size asat least one of the plurality of primary openings.

In this aspect, a number of secondary openings may be different than orthe same as the number of primary openings, optionally greater than thenumber of primary openings.

In this aspect, a plurality of secondary openings may be disposedaxially in between first and second axially adjacent primary openings.

In this aspect, a plurality of needles associated with a primary spinemay be adapted to be axially moved together as a unit relative to theassociated primary spine, and may optionally be secured to a rail thatis disposed within the primary spine. An inner surface of the primaryspine and an outer surface of a rail may at least partially define asecondary agent pathway through which a secondary agent is delivered.

In this aspect, the plurality of needles may be adapted to be incommunication with a first therapeutic agent source, and wherein aplurality of secondary openings may be adapted to be in communicationwith a second therapeutic agent source. First and second sources mayinclude therein the same agent or different agents.

In this aspect, the plurality of needles and a plurality of secondaryopenings may be adapted to be in communication with the same agentsource.

In this aspect, one or more secondary openings may comprise one or morediscontinuities in a wall of the primary spine in the region of theprimary spine that is disposed about the outer cylindrical surface ofthe balloon when inflated, wherein one or more discontinuities may be incommunication with the primary spine lumen to facilitate delivery of thesecondary agent through the one or more discontinuities in the primaryspine. One or more discontinuities in the wall of the primary spine maycomprise one or more laser-cut sections of the primary spine tofacilitate weeping of the secondary agent through the laser cut sectionsof the primary spine when the secondary agent is delivered into andthrough the primary spine lumen. The primary spines may further compriseone or more discontinuities in the wall of the primary spine in a regionof the primary spine that is proximal to the region that is disposedabout the outer cylindrical surface of the balloon when inflated.

In this aspect, the expandable infusion scaffold may further compriseone or more secondary spines that are disposed about the outercylindrical surface of the inflatable balloon, wherein the secondaryspines each comprise one or more secondary openings therethrough thatare not associated with a needle and are not adapted to deploy a needletherefrom, wherein the one or more secondary openings of the associatedsecondary spine are in communication with a secondary spine lumen tofacilitate delivery of the secondary agent through the secondary spinelumen and out of the one or more secondary openings of the secondaryspine.

In this aspect, the inflatable balloon may have a tapered proximal endand optionally tapered distal end, and wherein the cylindricalconfiguration is in between the tapered proximal and distal ends, andwherein one or more optional secondary spines are also disposed aboutthe tapered proximal end.

The one or more optional secondary spines may be arranged helicallyabout the cylindrical surface of the inflatable balloon.

The one or more optional secondary spines may be arranged axially aboutthe cylindrical surface of the inflatable balloon.

In this aspect, at least two or more secondary openings of the one ormore optional secondary spines may be circumferentially aligned.

In this aspect, at least two or more secondary openings of the one ormore optional secondary spines may be circumferentially offset oraxially offset.

In this aspect, at least two or more secondary openings of the one ormore optional secondary spines may be axially aligned.

In this aspect, a subset of the one or more optional secondary openingsmay be arranged in an at least partial helical configuration.

In this aspect, one or more secondary openings in the one or moreoptional secondary may comprise one or more discontinuities in a wall ofthe secondary spine in the region of the secondary spine that isdisposed about the outer cylindrical surface of the balloon wheninflated, wherein the one or more discontinuities are in communicationwith the secondary spine lumen to facilitate delivery of the secondaryagent through the one or more discontinuities in the secondary spine.One or more discontinuities in a wall of a secondary spine may compriseone or more laser-cut sections of the secondary spine to facilitateweeping of the secondary agent through the laser cut sections of thesecondary spine when the secondary agent is delivered into and throughthe secondary spine lumen.

In this aspect, one or more primary spines may be arranged helicallyabout the cylindrical surface of the inflatable balloon.

In this aspect, one or more primary spines may be arranged axially aboutthe cylindrical surface of the inflatable balloon.

In this aspect, a plurality of needles associated with each of the oneor more primary spines may be operatively coupled such that they areadapted to be moved axially as a group relative to the associatedprimary spine, optionally coupled to a rail within the primary spine.The optional rail may comprise a rail lumen that is in fluidcommunication with the plurality of needles.

In this aspect, each of the plurality of needles may be in fluidcommunication with a distinct fluid delivery lumen, which may optionallybe in fluid communication with a rail lumen.

In this aspect, one or more primary spines may extend along at leasthalf of the length of the portion of the balloon that has the inflatedcylindrical configuration.

In this aspect, a portion of the balloon that has the inflatedcylindrical configuration may have a length from 20 mm to 200 mm.

In this aspect, the expandable infusion scaffold may be attached to theinflatable balloon along at least a portion of a length of the scaffold.

In this aspect, the expandable infusion scaffold may not be attached tothe inflatable balloon.

In this aspect, one or more primary spines may each have a stiffnessthat is not constant along the length of the inflatable member.

In this aspect, a plurality of needles may be operatively coupled to anaxially moveable rail that is disposed within the associated primaryspine lumen, and wherein the rail may have a stiffness that is notconstant along the inflatable balloon.

In this aspect, one or more primary spines may comprise one or more ofnitinol, stainless steel, polymer, polyimide, or a braided member.

One aspect of the disclosure is an intravascular apparatus adapted fordelivery of a fluid. In this aspect, the apparatus may include aninflatable balloon having an inflated cylindrical configuration and anexpandable infusion scaffold.

In this aspect, the expandable infusion scaffold may comprise one ormore primary spines and/or one or more secondary spines, any of whichmay be disposed about an outer cylindrical surface of the inflatableballoon. In this aspect, the optional one or more primary spines may beany of the primary spines herein, and the optional one or more secondaryspines may be any of the secondary spines herein.

One aspect of this disclosure is a method of intravascular fluiddelivery and treatment.

In this aspect, the method may include advancing an intravascularapparatus to a target location within a vessel; inflating a balloontoward a cylindrical configuration to cause one or more primary spinesof an expandable infusion scaffold to expand toward a vessel wall and bedisposed about an outer cylindrical surface of the balloon; moving aplurality of needles axially within the one or more primary spines anddeploying the plurality of needles out of radial primary openings of theprimary spines such that tips of each of the plurality of needles pierceinto the vessel wall; and delivering a primary fluid agent out of theplurality of needles and into the vessel wall. Delivering a primaryfluid agent out of the plurality of needles and into the vessel wall maycomprise delivering the primary fluid agent into at least one of themedia and adventitia of the vessel wall.

In this aspect, the method may include delivering a secondary fluidagent out of one or more secondary openings to expose the vessel wall tothe secondary fluid agent. The method may include delivering thesecondary agent out of secondary openings that are in a primary spineand/or a secondary spine.

In this aspect, exposing a vessel wall to a secondary fluid agent maycomprise exposing the intimal layer of the vessel wall to the secondaryfluid agent, and optionally not exposing an adventitial layer to thesecondary fluid agent. In some applications, however, the secondaryfluid agent may passively infuse into the media and/or adventitia.

In this aspect, delivering a primary fluid agent may comprise deliveringan anti-restenosis agent out of the plurality of needles into the vesselwall.

In this aspect, delivering a secondary fluid agent may comprisedelivering an anti-recoil agent to expose the vessel wall to theanti-recoil agent.

In this aspect, the primary fluid agent may be the same as a secondaryfluid agent.

In this aspect, delivering a secondary agent may be initiated before orsubsequent to when a plurality of needles are deployed from a primaryspine.

In this aspect, delivering a secondary agent may be initiated at a timeprior to delivering a primary fluid agent out of a plurality of needles.

In this aspect, delivering a secondary agent may occur while the primaryfluid agent is being delivered out of the plurality of needles.

In this aspect, delivering a secondary agent may be initiated at a timesubsequent to delivering the primary fluid agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side view of a distal region of an exemplary infusion deviceincluding an expandable scaffold in an expanded configuration.

FIG. 2A is a side view of a distal region of an exemplary infusiondevice including an expandable scaffold in an expanded configuration.

FIG. 2B is a side view of a distal region of an exemplary infusiondevice from FIG. 2A with needles deployed from elongate spines of thescaffold.

FIG. 3A is an end view of a distal region of an exemplary infusiondevice with an inflatable member inflated.

FIG. 3B is an end view of a distal region of the exemplary infusiondevice in FIG. 3A, shown with needles deployed.

FIG. 4A is an end view of a distal region of the exemplary infusiondevice from FIG. 3A, shown within an exemplary vessel.

FIG. 4B is an end view of a distal region of the exemplary infusiondevice in FIG. 3A shown with needles deployed and within an exemplaryvessel.

FIG. 5 is a distal region of an exemplary infusion device illustratingneedles deployed from spines of an expandable scaffold.

FIGS. 6A, 6B, 6C and 6D illustrate views of portions of an exemplaryneedle subassembly or rail track sub-assembly.

FIG. 6E illustrates an exemplary needle secured to a fluid deliverylumen.

FIG. 6F illustrates an exemplary rail.

FIG. 6G illustrates a portion of an exemplary infusion spine.

FIG. 7A illustrates a top view of an exemplary needle or rail tracksub-assembly.

FIG. 7B illustrates a side view of the exemplary needle or rail tracksub-assembly from FIG. 7A.

FIG. 8 is a side view of a plurality of exemplary needles deployedoutward from an infusion spine.

FIG. 9 illustrates an exemplary cross section of an exemplary needle orrail track sub-assembly.

FIG. 10 illustrates an exemplary cross section of an exemplary needle orrail track sub-assembly.

FIGS. 11A and 11B illustrate side and end views, respectively, of anexemplary infusion device in a collapsed lower profile deliveryconfiguration.

FIGS. 11C and 11D illustrate side and end views, respectively, of theexemplary infusion device from FIGS. 11A and 11B in an expandedconfiguration with needles deployed.

FIG. 12 illustrates a distal region of an exemplary infusion device inan expanded configuration, with regions that are more flexible thanother sections of the spine.

FIG. 13 is a side view illustrating an exemplary infusion device,including a proximal region positioned to be disposed outside of apatient.

FIG. 14 is a side view of an exemplary proximal region of an exemplaryinfusion device, including an exemplary actuator.

FIGS. 15A and 15B are proximal end views of a proximal external regionof an exemplary infusion device.

FIG. 16 is a side view illustrating an exemplary manner in which aninflatable member may be secured to a catheter shaft.

FIGS. 17A-17C illustrate side and end views, respectively, of anexemplary apparatus including a plurality of primary spines thatcomprise a plurality of primary openings and one or more secondaryopenings.

FIG. 18 illustrates an exemplary primary spine that comprise a pluralityof primary openings and one or more secondary openings, and an exemplaryaxially movable rail assembly within the primary spine.

FIGS. 19A-19D illustrate exemplary primary spines with exemplary primaryand secondary opening configurations and relative positions.

FIG. 20 illustrates an exemplary apparatus in an expanded configuration,the apparatus including one or more primary spines with needlesdeployed, and one or more secondary spines.

FIG. 21 illustrates an exemplary secondary or primary spine, with adiscontinuity in the wall of the spine, wherein the discontinuity mayfacilitate delivery of a second agent out of the spine.

DETAILED DESCRIPTION

The disclosure herein is related to methods, devices and systems for thedelivery of one or more therapeutic agents for the treatment ofperipheral artery disease. The methods, devices and systems herein areadapted to efficiently and reliably deliver the desired dose of an agentto a target region of adventitial tissue, particularly compared toexisting drug coated balloons (DCB), drug eluting stents (DES), andsingle-needle delivery devices. Additionally, the methods, devices andsystems herein are also adapted to efficiently and reliably deliver thedesired dose of an agent to a shallower depth in the vessel wall, suchas to the intimal layer. When treating PAD, it may be beneficial todeliver first and second agents to different depths within the vesselwall for different therapeutic purposes. For example only, ananti-recoil therapeutic agent may be exposed to the vessel wall,optionally into the intima, to provide an anti-recoil therapy, while ananti-restenosis therapeutic agent may be delivered into the media and/oradventitia to provide an anti-restenosis therapy. A therapeutic agentdelivered deeper into the vessel wall is generally referred to herein asa primary agent, while a therapeutic agent exposed to the vessel walland delivered to a relatively shallower region of the vessel wall isgenerally referred to herein as a secondary agent.

Primary agents herein may comprise a single agent, or they may includemore than one type of agent either combined or separate. Deliveringprimary agents out of the needles may include delivering more than onetype of agent out of the needles in combination and simultaneouslyand/or delivering more than one type of agent separately. For exampleonly, a primary agent may comprise first and second primary agents (ormore), and wherein the first primary agent may be delivered before thesecond primary agent.

Similarly, secondary agents herein may comprise a single agent, or theymay include more than one type of agent either combined or separate.Delivering secondary agents out of at least one of the secondary andprimary openings may include delivering more than one type of agent outof the openings in combination and simultaneously and/or delivering morethan one type of agent separately. For example only, a secondary agentmay comprise first and second secondary agents (or more), and whereinthe first secondary agent may be delivered before the second secondaryagent.

Infusion devices herein may include a plurality of deployable needles,which are spaced axially (also referred to herein as longitudinally) andcircumferentially apart around the infusion device, allowing moreuniform circumferential coverage and a greater span of tissue along thelesion length to be targeted with a primary agent without having to movethe infusion device within the vessel. It is of course understood thatany of the treatments herein may include delivering a primary agent,after which the infusion device may be moved to a different locationwithin the vessel before again delivering the same or a differentprimary agent, which is described above.

Additionally, infusion devices herein may be positioned against a vesselwall upon application of a radially outward force, which is generallydescribed herein as a force applied by an inflatable member or balloon,although it is conceivable that non-inflatable members may alternativelybe used. After the infusion device is apposed against the vessel wall,the needles can be deployed outward such that they pierce through thevessel wall and optionally into the adventitia layer of the vessel wall.Once the needles have been advanced into the wall and optionally intothe adventitia, the desired therapeutic primary agent is deliveredthough the needles, out of the needles, and into the primary targettissue within the vessel wall. In some methods, the volume and rate ofinfusion may be controlled based on one or more of a desired lesionlength and/or desired volume of agent infusion.

One or more of any of the following primary therapeutic agents or typesof agents, including but not limited to any combination thereof, may bedelivered from the infusion devices herein during any of the methods ofuse herein: antiplatelet agents; anti-inflammatory agents;antiproliferative drugs as referred to as cell-proliferation inhibitors;immunosuppressants such as mTOR and IMDH inhibitors; anticoagulationdrugs; antithrombotic agents; lipid-lowering drugs;angiotensin-converting enzyme (ACE) inhibitors; regenerative agents; andstem cells. While the disclosure herein focuses on PAD, the device andsystems herein may be used to treat alternative conditions, such as, forexample only, chronic obstructive pulmonary disease (“COPD”), which isdescribed in U.S. Prov. App. No. 62/953,342, which is incorporated byreference herein in this regard. Agents that may be delivered to treatCOPD, for example, include but are not limited to anti-inflammatoryagents, receptor antagonists, and neurotoxins.

The disclosure that follows describes non-limiting exemplary infusiondevices that are adapted and configured to deliver one or more primarytherapeutic agents and provide one or more of the advantages set forthherein, such as efficiently delivering a desired volume or dose to atarget region of tissue in the vessel wall. While FIGS. 1-16 mayillustrate examples of infusion devices that do not include secondaryopenings, it is understood that any suitable feature or aspect of FIGS.1-16 and the disclosure that now follows may be incorporated into anyapparatus and method of use herein that includes both primary openingsand one or more secondary openings, whether those one or more secondaryopenings are disposed in a primary spine or an optional secondary spine.It is understood that any of the infusion spines in FIGS. 1-16 may beconsidered a primary infusion spine (or primary spine) even if notexpressly referenced as a primary spine. It is also understood thatcertain disclosure that follows (with reference to FIGS. 1-16 ) that isgenerally related to a spine may, however, apply to secondary spinesherein, and may be incorporated into any suitable secondary spineherein. For example, disclosure that follows related to a material thatmay be used for spines herein may be applicable to primary and/orsecondary spines. Additionally, for example, disclosure that followsrelated to openings in a spine may also be applicable to any of thesecondary spines herein.

In this disclosure, the phrases “primary spine” and “primary infusionspine” (or similar phrases) refer to infusion spines that include atleast one primary opening from which a needle is deployed. Primaryspines herein may also include one or more secondary openings (describedin more detail below), wherein the one or more secondary openings arenot associated with a needle and thus a needle is not and cannot bedeployed from a secondary opening. In this disclosure, the phrases“secondary spine” and “secondary infusion spine” (or similar phrases)refer to infusion spines that do not include any primary openings from awhich a needle can be deployed. Secondary spines herein thus include oneor more secondary openings and do not include any primary openings.

FIG. 1 illustrates a distal region of an example of an infusion device.Infusion device 100 includes an expandable infusion scaffold 110 thatincludes at least first and second primary infusion spines 112 a, 112 b,and 112 c (three shown in this example), which are shown in FIG. 1 inexpanded configuration with the infusion needles deployed. Unlessindicated herein to the contrary, the infusion spines herein may also bereferred to as a plurality of infusion spines. Infusion spines (bothprimary spines and optional secondary spines) are sized, positioned, andconfigured to be expandable by a generally radially outward force, whichin this example is applied by an inflatable member 150. Any of theinflatable members herein may include one or more of a compliantmaterial (e.g., polyurethane or silicone), a non-compliant material(e.g., polyester or nylon), or a semi-compliant material. As shown, theprimary infusion spines 112 a, 112 b and 112 c are circumferentiallyspaced about an outer surface of the inflatable member 150 with a longaxis (LA) of the infusion device when the primary spines are expanded.The long axis in this embodiment is also a long axis of the inflatablemember 150. In this example, the primary spines are parallel (orsubstantially parallel) with the long axis of the infusion device 100and the inflatable member 150 when expanded, as shown. As used herein,the phrase substantially parallel in this context includes slightdeviations from being parallel and includes spines that haveconfigurations that still facilitate the efficient and effectivedelivery of therapeutic agent to the desired tissue. One of skill in theart will appreciate that substantially parallel as used in this contextallows for some deviation from strictly parallel, such as at an angle offive or ten degrees relative to a long axis, for example.

Any of the primary spines shown in FIGS. 1-2B may be replaced by anoptional secondary spine, which are described elsewhere herein.

In this example the inflatable member has a cylindrical configurationwhen expanded, as shown. The term cylindrical as used in this contextincludes configurations that approximate a cylinder even if notperfectly cylindrical, which may be the case if a plurality of infusionspines are attached or engaging an outer surface of the inflatablemember and the balloon does not have a perfectly cylindricalconfiguration when expanded. Additionally, an inflatable member maystill be considered to have a cylindrical configuration even if theinflatable member has at least one end region that is tapered or has anyother configuration that is not orthogonal with the long axis, such asthe tapered distal and proximal ends of the inflatable member that areshown in FIG. 1 . Additionally, for example, an inflatable member with ageneral dumbbell configuration may be considered to have a cylindricalconfiguration. Additionally still, when the description herein describesinflatable members having cylindrical configurations when expanded, itrefers to the configuration the inflatable member would take after beingexpanded outside of a patient. This is meant to clarify that whenexpanded or inflated within a vessel of the patient, there may be one ormore anatomical restrictions that prevent the inflatable member fromtransitioning to the cylindrical configuration it would assume ifexpanded outside of a patient, such as the configuration of the vesselwall in which the infusion device is placed. In both scenarios, theinflatable member in these examples is considered to have a cylindricalconfiguration when expanded.

The primary and optional secondary infusion spines herein may beconnected (directly or indirectly) to the inflatable member, such as bybonding, adhesion, or using any other suitable technique for securingthe spines to an inflatable member. In any of the examples herein, thespines may alternatively not be connected to the inflatable member, butthey are still adapted to be expanded by inflation of the inflationmember due to their proximity to the inflatable member. For example, theexpandable infusion scaffold may be delivered on or over a balloon-basedcatheter in a compressed low-profile delivery state, and then expandedby dilating the balloon-based catheter at the intended location withinthe vessel.

FIG. 1 shows an exemplary inflatable member 150 and an expandableinfusion scaffold 110, both in an expanded state or configuration. Fordelivery, the expandable infusion scaffold is in a collapsed deliveryconfiguration in which the primary infusion spines are closer toadjacent primary spines than in the expanded state, such as shown inFIG. 11A. It is understood that FIGS. 11A-11D are an alternativeembodiment, and the reference to FIG. 11A is meant to illustrate aninfusion scaffold in a collapsed delivery configuration (or at least aconfiguration in which it is not fully expanded). During delivery, theinflatable member is also in a lower profile unexpanded (and uninflated)collapsed delivery configuration. The internal volume of the inflatablemember is also less in the delivery state than in the deployed state.Once the infusion device is delivered to the target location within avessel, the inflatable member is inflated, which pressurizes theinflatable member. This expansion of the inflatable member causes theinflatable member to increase in a radial dimension and apply a force tothe plurality of primary infusion spines that are disposed around theinflatable member. This causes the primary spines to expand radially andwhich also causes the relative circumferential distance between theprimary spines to increase, an example of which is shown in FIG. 11C.The expandable infusion scaffold is thus expanded towards the vesselwall by inflating and expanding the inflatable member.

The inflatable member may have a variety of collapsed states orconfigurations. For example, the inflatable member may be folded in oneor more locations to facilitate its collapse, while in other embodimentsthe inflatable member may not have a particular or well-definedcollapsed state.

The inflatable members herein are sized and configured such that whenexpanded, the plurality of infusion spines (primary spines and optionalsecondary spines) will be moved radially outward and in contact orsubstantial contact with the vessel wall. It is understood that due tosome variability in vessel wall size, some portion of any of theinfusion spines may not make direct contact with vessel wall. Theinflatable member may be sized such that it may have a deployed diameterthat is larger than an intended vessel size to help ensure that theinfusion spines are in contact or substantial contact with the vesselwall. Maintaining sufficient pressure in the inflatable member such thatthe infusion spines are in substantial contact with the vessel wall canhelp support the needles as they are deployed and pierce through thevessel wall, which is described in more detail below.

Any of the expandable scaffolds herein may have infusion spines (primaryand optionally secondary) that are optionally equidistantly spaced apartalong their lengths, an example of which is shown in FIG. 1 . Forexample, two infusion spines may be spaced apart 180 degrees around theinflatable member when the scaffold and infusion spines are expanded.Alternatively, three infusion spines may be spaced apart 120 degreesaround the inflatable member when the scaffold and infusion spines areexpanded. Alternatively, four infusion spines may be spaced apart 90degrees around the inflatable member when the infusion spines areexpanded, and so forth. In the collapsed delivery state, the infusionspines of the scaffold can also have the same general relativerelationship even though they are closer together and not spaced as farapart.

While equal spacing between spines may in some applications provide morecomplete delivery of an agent to target tissue around or in the vesselwall, in alternative examples the infusion spines may not all beequidistantly spaced apart around the inflatable member.

FIG. 16 illustrates a distal portion of an exemplary infusion device,wherein the expandable scaffold is not shown for clarity. In thisexample, the infusion device includes an inflatable member 1650, whichis shown inflated. A distal end of inflatable member 1650 is coupled toinner shaft or member 1670, and a proximal end of inflatable member 1650is coupled to outer shaft 1672. The inner and outer shafts 1670 and 1672define therebetween inflation fluid pathway 1674, which is in fluidcommunication with an interior volume of inflatable member 1650. Theinner volume of inflatable member 1650 and fluid pathway 1674 are influid communication with a fluid inflation port, such as inflation port1333 or inflation port 1433 shown in FIGS. 13 and 14 , and which aredescribed in more detail below. Alternatively, the inflatable membersherein may be secured to the infusion device in a manner that may be thesame or similar to known balloon angioplasty catheters, examples ofwhich are described in U.S. Pat. No. 4,782,834 and U.S. Ser. No.10/086,175, and which are incorporated by reference herein for allpurposes. Any of the fluid delivery devices herein that include one ormore primary spines and optional secondary spines may include featuresshown in and described relative to FIG. 16 .

Once the expandable inflation scaffold is expanded and in contact with(or at least substantially in contact with) or directly adjacent thevessel wall, each of a plurality of needles within a primary spine aredeployed outward from a radial opening in the primary infusion spine, anexample of which is labeled in FIG. 5 as opening 516. FIG. 1 illustratesa plurality of needles deployed from the expandable infusion scaffold,and in this example shows a plurality of needles deployed from each ofthe primary infusion spines. Needles 114 a are shown deployed fromprimary infusion spine 112 a. Needles 114 b are shown deployed fromprimary infusion spine 112 b. Needles 114 c are shown deployed fromprimary infusion spine 112 c. In this merely illustrative example, thereare three needles shown deployed from each of the primary infusionspines. In any of the embodiments herein, each primary infusion spinemay be associated with from two to fifty needles, all of which can bedeployed from a radial opening in the primary spine. As used in thiscontext, the term associated refers to needles that are within anyparticular primary spine in a delivery state, and are deployable fromthat particular primary spine to pierce the vessel wall.

When this disclosure refers to an infusion spine (primary and optionalsecondary), it is generally referring to one of the infusion spines ofthe expandable scaffold. Additionally, when a feature is described withrespect to any particular or individual infusion spine, it is understoodthat all of the infusion spines of any particular scaffold may also haveany or all of those features. The phrase infusion spine herein may beused interchangeably with the term spine.

The needles in any primary infusion spine herein are generally axiallyspaced apart, as shown in the examples of FIGS. 1, 2B and 5 , forexample. Spacing the needles axially apart can provide maximum coverageof the therapeutic agent along the length of the target lesion, whichcan increase the volume of tissue that may be targeted by using theinfusion devices herein. Additionally, by having a plurality of primaryinfusion spines spaced around or about the device, with each infusionspine having a plurality of axially-spaced needles deployable therefrom,the infusion devices herein can ensure or increase the likelihood ofdelivering the agent to as much target tissue around the vessel aspossible without having to rotate or move the infusion device to providethe desired circumferential coverage of the infused agent. It is ofcourse understood that the infusion devices herein may also be moved inbetween episodes of agent delivery into the vessel wall. In theseinstances, the needles may be retracted, and the infusion device can bemoved to a different location within the vessel or to a differentvessel. The inflatable member and the scaffold are generally collapsed(at least partially) before moving the infusion device to a newlocation. It is also understood that devices herein may include a singleprimary spine, wherein a plurality of needles are associated with thesingle primary spine.

In any the infusion devices herein, any two axially spaced needlesassociated with a primary infusion spine may be spaced from 1 mm to 40mm apart, such as from 5 mm to 35 mm apart, such as from 10 mm to 30 mmapart, such as from 15 mm to 20 mm apart.

In any of the infusion devices herein, any adjacent pair of three ormore needles that are associated with a single primary infusion spinemay be equidistantly spaced apart axially. Alternatively, any adjacentpair of three or more needles associated with a single primary infusionspine may not be equidistantly spaced apart axially. It is of courseunderstood that any primary spine herein may only be associated with twoneedles, and this paragraph is only related to primary spines that maybe associated with more than two needles.

In some illustrative embodiments, any of the infusion devices herein mayinclude from six to 50 needles total. For example, an infusion devicewith three primary spines, each associated with two needles, would havesix needles total.

FIG. 1 illustrates an example in which primary infusion spines do nothave the same lengths and do not have distal ends that extend as fardistally as at least one other distal end. In this example, the lengthsof all of the primary spines that are shown are different, and none oftheir distal ends are axially aligned. In any of the infusion devicesherein, any of the primary spines may have lengths that are the samesuch that their distal ends are axially aligned with any other spinedistal end. In this context, the term length generally refers to theportion of the spine that overlaps with the inflatable member ratherthan a portion of a spine that may also extend proximally from theinflatable member.

The needles in different primary spines may or may not be axiallyaligned. For example, the exemplary needle placement in FIG. 1 showsnone of the needles being axially aligned with needles incircumferentially adjacent primary spines. Any of the needles in thedifferent primary infusion spines, however, may be axially aligned.Likewise, the primary infusion spines may also be axially aligned. Forexample, the infusion device may have rows of needles, with the rowsspaced apart axially along the length of the infusion device, an exampleof which is shown in FIG. 5 . A row as used in this context refers totwo or more needles in different primary spines that are axiallyaligned. The apertures in the top and bottom spines in FIG. 11C areaxially aligned, which will cause the needles associated with the topand bottom primary spines in FIG. 11C to be axially aligned whendeployed.

In any of the infusion devices herein, the number of needles associatedwith each of the primary infusion spines may be the same. FIG. 1 showsan example of this, with three needles per primary infusion spine. Inalternatives, the number of needles in each of the primary infusionspines may not be the same. For example, one primary spine may beassociated with two needles, while a second primary spine may beassociated with three needles. Any of the infusion devices herein mayhave an expandable scaffold with a plurality of primary spines,optionally wherein none of the primary spines has the same number ofneedles as any other primary spine.

FIGS. 2A, 2B, 3A, 3B, 4A and 4B illustrate an exemplary infusion device200 with an expandable infusion scaffold 210 that includes a pluralityof primary infusion spines 212 (one labeled as 212 a). Any suitablefeature from FIG. 1 or described elsewhere herein may be incorporatedinto infusion device 200. Infusion device 200 also includes inflatablemember 250 that when inflated and expanded causes the expandableinfusion scaffold 210 to expand, described in more detail elsewhereherein. Each of the plurality of primary infusion spines includes aplurality of radial openings or windows 216 (shown in FIG. 2A), throughwhich the plurality of needles 214 (labeled as 214 a, 214 b and 214 cfor the different spines) extend when deployed. FIGS. 2A (side view), 3A(end view) and 4A (end view in an exemplary vessel 275) show theinfusion device after the inflatable member 250 has been inflated butwith the needles not yet deployed, while FIGS. 2B, 3B and 4B showexemplary needles 214 deployed through the openings in the primaryinfusion spines 212. FIG. 4B illustrates the needles 214 piercing into(which may be referred to as “through”) the vessel wall 275 andextending into the adventitia “A.” FIGS. 4A and 4B illustrate intimal“I,” medial “M,” and adventitial “A” layers of the vessel. Any otherdisclosure herein from any other example may be incorporated into theexamples in FIGS. 2A-4B. Any of the disclosure related to FIGS. 2A-4Bmay be incorporated by reference into suitable embodiments herein thatinclude scaffolds with both primary and secondary openings.

Generally, the infusion spines herein include a lumen and a plurality ofopenings or windows therein, such as openings 216 in FIG. 2A. Theneedles herein are generally disposed within a primary infusion spine ina delivery state in which the needle tips are radially constrained bythe spine, and are deployed from the primary infusion spine out of oneof the needle openings in response to axial movement relative to thespine to pierce the vessel wall. The needles herein may be disposedwithin and deployed from the infusion spines in a variety of ways.Additionally, the needles herein may be in fluid communication with afluid source in a variety of ways. The examples below are meant to beillustrative. The needles herein associated with a primary infusionspine may be deployable at the same time. The needles herein associatedwith an infusion spine may be deployable by moving them together as aunit, such as if they are coupled to a common axially movable memberwithin the primary spine. The needles herein associated with a primaryinfusion spine may be separately deployable from within the primaryspine.

Each of the plurality of needles associated with a primary infusionspine may be coupled to an axially moveable member that is disposedwithin the infusion spine, such that axial movement of the axiallymoveable member relative to the primary infusion spine causes the axialmovement of the needle relative to the primary infusion spine.

In some embodiments herein, the needles associated with a primaryinfusion spine are all adapted to move together in unison upon the axialmovement of an axially movable member, which may be referred to in thiscontext as a common axially moveable member. In some alternatives, theneedles associated with a primary infusion lumen (or primary spinelumen) may be axially moved independently from one another, such as wheneach needle is coupled to its own or individual axially moveable memberwithin the primary spine.

In some embodiments the axially moveable member (which may be referredto as a rail or rail track) is a separate structure that does notspecifically define a fluid lumen, although in these examples theaxially moveable member may house therein one of more fluid lumens thatare in fluid communication with one or more needles. Additionally, inthese embodiments, one or more fluid lumens within the axially movablemember may also be moved axially relative to the infusion spine inresponse to axial movement of the axially moveable member.

FIG. 5 illustrates an exemplary infusion device 500, which mayincorporate any of the disclosure related to infusion device 100 shownin FIG. 1 or any other feature described herein. Infusion device 500includes an expandable infusion scaffold 510, which includes a pluralityof primary infusion spines 512 a, 512 b (a third infusion spine 512 c isnot visible in the side view of FIG. 5 ). The primary infusion spines512 a and 512 b each include a plurality of openings 516 through whichthe needles are deployed. In this example, each of the primary spines isassociated with three needles as shown, but more or fewer may beassociated with each primary infusion spine as is described elsewhereherein.

FIGS. 6A-6F illustrates exemplary features of an exemplary needlesubassembly 620 (any of which may be referred to herein as a rail tracksubassembly, and vice versa), with the primary infusion spine not shownfor clarity. Rail track subassembly 620 is configured to both move theneedles to deploy them from the primary infusion spine openings, as wellas provide housing for one or more fluid lumens that are in fluidcommunication with one or more needles, and such fluid communication tothe needles to deliver the agent into the vessel wall when the needlesare deployed from the openings in the primary infusion spine. FIG. 6Eillustrates an exemplary needle 614 a coupled to fluid lumen 622 with anoptional coupler 624. In other embodiments any of the needles herein maybe directly connected to a fluid lumen. The needle 614 a and fluid lumen622, as shown in FIG. 6E, are then positioned within rail 623, which isshown alone in FIG. 6F. Rail 623 is an example of an axially movablemember that is configured to be axially moved to cause the axialmovement of a plurality of needles. Rail 623 is also sized andconfigured to house therein one or more fluid lumens, in this case fluidlumen 622″ and fluid lumen 622′″, as shown in FIG. 6D. As shown in FIG.6D, in this example each needle is in fluid communication with adistinct or individual fluid lumen, but they are coupled to rail 623such that they move axially together in unison when rail 623 is moved.With respect to FIG. 6E, each needle is coupled to an individual fluidlumen as shown, then advanced through rail 623 and coupled thereto, asis shown in FIGS. 6A-6D. FIG. 6D illustrates one example of a pluralityof individual fluid lumens 622″ and 622′ housed or disposed within alumen of rail 623. Rail 623, at least in this exemplary embodiment, canbe moved axially to axially move all of the needles, as well as serve tohouse the individual fluid lumens therein.

The needle subassembly 623 shown in FIG. 6A can be then positioned inone of the primary infusion spines, such as by front loading or backloading. When the needle subassembly 620 is loaded into a primaryinfusion spine, the needles will deflect radially inward towards theopenings 621 that are labeled in FIG. 6F, and the needle subassembly maybe positioned in the primary infusion spine such that the needles andneedle tips are just proximal to the infusion spine openings 616 (withthe needle tips radially constrained by an inner surface of the spine),labeled in the exemplary primary spine 612 shown in FIG. 6G.

Any of the needles herein may be formed with a natural bias towards adeployed configuration in which the needles extend at least partiallyradially outward, such as is shown in FIGS. 6A, 6B, 6C, 6D and 6E. Whenthe needles are collapsed radially down or inward for delivery, they mayor may not have a perfectly linear configuration due to their naturallybiased and curved deployed configuration. When collapsed for delivery,any of the needles may retain a slight curvature in their configuration,with their tips radially constrained by the inner surface of the spine.

The use of the term rail herein does not necessarily impart anystructural limitations. The rails herein may be elongate members thatare sized and adapted to be moveable within an infusion lumen tofacilitate the movement of one or more needles. Any of the rails hereinmay be a tubular member or partial tubular member, such as rail 623shown in FIGS. 6A-6F, or any other elongate member (with or without alumen) that is sized and configured for axial movement within a spine.

As part of an exemplary manufacturing of a rail track assembly, theneedle and corresponding fluid lumen may be front-loaded through therail. A coupler (e.g., 624″ or 624′″), if used, may be secured (e.g.,bonded, welded, or otherwise secured thereto) to the needle and fluidlumen as shown in FIG. 6E. The rail openings 621 may be formed byremoving sections of the material of rail 623, which may itself be anelongate tubular member, such as a stainless steel or nitinol tubularmember.

Each primary infusion spine in the exemplary infusion device shown inFIGS. 6A-6F is associated with at least three subcomponents orsubassemblies—the infusion needle(s), the infusion lumen(s), and therail track subassembly housing the respective infusion needle(s) andinfusion lumen(s).

Any of the disclosure related to FIGS. 6A-6G may be incorporated byreference into any of the suitable disclosure herein related to devicesand methods of use that includes scaffolds that comprise both primaryand secondary openings.

In any of the examples herein, any of the fluid delivery lumens may havean outer diameter from 0.001 inches to 0.01 inches, for example. Fluiddelivery lumens herein may also be referred to herein as fluid lumens.

In any of the examples herein, any of the axially moveable members (suchas any of the rails) may have an outer diameter from 0.005 inches to0.05 inches.

In any of the examples herein, any of the axially moveable members mayhave openings (e.g., openings 621) that are axially spaced from 5 mm to80 mm apart, such as from 10 mm to 50 mm

In any of the examples herein, any of the axially moveable members mayhave openings (e.g., openings 621) that have a length from 2 mm to 20mm.

In any of the examples herein, any of the spines (primary spines andoptional secondary spines) may have an outer diameter from 0.01 inchesto 0.08 inches.

In any of the examples herein, any of the spines (primary spines andoptional secondary spines) may have openings (e.g., openings 216, 516)that are axially spaced apart from 5 mm to 80 mm.

In any of the examples herein, any of the spines (primary spines andoptional secondary spines) may have openings (e.g., openings 216, 516)may have openings with a diameter or length dimension from 0.05 mm to 10mm.

FIGS. 7A and 7B, in top and side views, respectively, illustrate anexemplary rail track subassembly 720 (spine not shown for clarity), withthree exemplary needles in deployed configurations. Any of the featuresfrom assembly 620 of FIG. 6A may be incorporated into assembly 720. Railtrack subassembly 720 includes rail 723, which has openings 721therethrough (only one of which is labeled in FIG. 7A), and in thisexample there are three openings 721 in rail 723. Needles 714 a arecoupled to individual and distinct fluid lumens 722, optionally viacouplers 724 but alternatively directed connected thereto, which may besecured to rail 723 to secure the needle to the rail 723 and provideunitary axial movement of the needles 714 (which are individuallylabeled as 714 a′, 714 a″, and 714 a′″).

FIGS. 7A and 7B also illustrate how fluid lumens may extend through therail 723 lumen. For example, fluid delivery lumen 722′ is in fluidcommunication with needle 714 a′ and extends through rail 723. Fluiddelivery lumen 722′ extends adjacent to central needle 714 a″ and fluiddelivery lumen 722″, as shown in the central regions of FIGS. 7A and 7B.In the proximal region shown in FIGS. 7A and 7B, all three fluiddelivery lumens 722′, 722″ and 722′″ are adjacent one another within therail 723. Any of the fluid delivery lumens herein may include a bend ordeviation in its path such that it can pass next to a different needleand its associated fluid delivery lumen, which is shown in FIGS. 7A and7B. In this manner, the needles can extend in the same direction fromthe primary spine, which can be seen in the top view of FIG. 7A. In thetop view of FIG. 7A, the needles are all extending upward, or out of thepage.

Any of the disclosure related to FIGS. 7A and 7B may be incorporated byreference into any of the suitable disclosure herein related to devicesand methods of use that includes scaffolds that comprise both primaryand secondary openings.

In some embodiments, the axially movable member may also at leastpartially define a fluid lumen that is in fluid communication with oneor more needles, such as in the example shown in FIG. 8 . FIG. 8illustrates an exemplary needle assembly 820 shown within an exemplaryprimary spine 812 a, which includes top or radially outward openings816. Needle assembly 820 is an axially movable member that in thisembodiment also at least partially defines a fluid delivery lumen asshown that is in fluid communication with all of the needles 814 a.Needles 814 a are shown in their deployed configuration (tissue notshown for clarity) extending out of the spine openings 816. Any otherfeature from any other example herein may be incorporated into thefeatures shown in FIG. 8 , including use with any other inflatablemember herein. Any of the disclosure related to FIG. 8 may beincorporated by reference into any of the suitable disclosure hereinrelated to devices and methods of use that includes scaffolds thatcomprise both primary and secondary openings.

In some alternative embodiments, the needles may be extending from aprimary infusion spine when the infusion device is in a collapseddelivery configuration. FIGS. 11A-11D illustrate such as example, withinfusion device 1100 shown in a collapsed configuration in FIGS. 11A and11B, and expanded in FIGS. 11C and 11D (the needles are shown only inFIGS. 11B and 11D for clarity). FIGS. 11A and 11C are side views, andFIGS. 11B and 11D are end views. As shown in FIG. 11B, needles 1114 aare tucked within folded sections of inflatable member 1150 in thecollapsed delivery state. Inflatable member 1150 may include sections ofthe material that are easier to fold to facilitate the predictablefolding of the balloon around the primary infusion spines and needles,as shown in FIG. 11B. An exemplary guidewire 1154 disposed withinguidewire lumen 1155 is also shown, which may be used to deliver any ofthe infusion devices herein using known guidewire delivery techniquesand methods. FIGS. 11A and 11B also illustrate generally collapseddelivery configurations of spines and an inflatable member, which may beincorporated with any of the other examples herein wherein the needlesare not deployed until the inflatable member is expanded. The inflatablemembers herein need not, however, collapse in a predictable manner as isshown in FIG. 11B.

Any of the disclosure related to FIGS. 11A-11D may be incorporated byreference into any of the suitable disclosure herein related to devicesand methods of use that includes scaffolds that comprise both primaryand secondary openings.

Any of the lumens herein (e.g., infusion spine lumen, rail lumen, and/orfluid lumen) may have or benefit from having one or more regions withsufficient flexibility to allow for the infusion device to be deliveredto the target location in the vasculature. For example, any of thelumens herein may incorporate a tubular member having a wall with one ormore regions with one or more discontinuities, such as cuts, therein(e.g., a laser cut or other technique) that imparts some degree offlexibility along at least a portion of its length. Discontinuities suchas cuts made in a wall of any tubular member herein may be in the formof, for example without limitation, including combinations thereof, anat least partial spiral pattern, an at least partial brick pattern, orany other pattern that increases the flexibility of the wall of thelumen. More than one pattern may be implemented in the wall of any lumen(spine lumen, rail lumen, fluid delivery lumen, etc.), and the shape orconfiguration of a cut pattern may change along the length of the lumen.As is discussed elsewhere herein, discontinuities (e.g., laser cuts) ina wall of a primary or secondary spine may be considered as a secondaryopening through which a secondary agent may be delivered to the vesselwell.

Any of the fluid lumens herein may optionally include a non-permeablemembrane on one or both of an inside or the outside, such as anelastomeric membrane (e.g., urethane, silicone, or hydrogel), which canprevent fluid from leaking therethrough. For example, any lumens thatmay include or more discontinuities (e.g., cuts) therein (e.g., lasercut tubes) may include one or more membranes secured thereto to maintainintegrity.

Any of the lumens herein may comprise, for example, any combination ofnitinol, stainless steel, polymer tubing, polyimide, braided tubing, orother structural material. Any of the lumens herein may be constructedto provide the desired fluid integrity and/or flexibility when beingdelivered to the target delivery site.

In some examples, sections of primary infusion spine(s) in betweenneedle regions may be more flexible to provide more flexibility at thoselocations, while the primary spine regions where the needles aredeployed may have relatively higher stiffness to aid the needle piercingthrough tissue or calcifications. FIG. 12 illustrates an exemplaryinfusion device 1200, with inflatable member 1250 and scaffold 1210 inexpanded configurations or states. Scaffold 1210 includes a plurality ofprimary spines 1212 a and 1212 b. Primary spine region 1207 may beconfigured to be more flexible than distal region 1209 and proximalregion 1211 that are axially adjacent to region 1207. Needles may bepresent in regions 1209 and 1211, for example. Each primary spine mayhave a plurality of regions 1207 that are more flexible that othersections of the primary spine, any of which may be axially spaced apartwith less flexible primary spine regions in between, which is describedin more details with respect to FIG. 13 . Any of the disclosure relatedto FIG. 12 may be incorporated by reference into any of the suitabledisclosure herein related to devices and methods of use that includesscaffolds that comprise both primary and secondary openings.

FIG. 13 illustrates an exemplary infusion device 1300 shown withexpandable member 1350 in an expanded configuration and a plurality ofneedles 1314 (only one of which is labeled) deployed from openings inprimary spines 1312 (only one spine is labeled, and there may beadditional spines and associated needles). In this example, the primaryspines include first regions 1312′ at and around the locations whereneedles extend through openings therefrom, and regions 1312″ axiallyadjacent and optionally in between first regions 1312′. First regions1312′ may be considered to include the primary spine openings from whichthe needles extend. First regions 1312′ may be less flexible thanregions 1312″. This arrangement may provide sufficient stiffness to theprimary spine region where the needle extends therefrom, helping theneedle pierce through tissue (or calcifications), while regions 1312″can provide more flexibility for tracking and delivery. Any of theprimary spines herein may include first and second regions withdifferent stiffness as in the example of FIG. 13 .

As is set forth herein, the scaffold may or may not be attached to theinflatable member. In examples in which the scaffold (including thespines) is attached to the inflatable member, the spines (primary andoptional secondary) may be secured to the inflatable member along theirentire length, or less than their entire length. In some devices, theindividual spines may be attached to the inflatable balloon at aplurality of axially spaced sections or regions along its length, andnot directly attached to the inflatable member at one or moreaxially-spaced sections or regions along its length. For example only,with respect to FIG. 13 , the plurality of spines may be attached to theinflatable member 1350 in regions 1312′, but not attached directly tothe inflatable member 1350 in regions 1312″. Not directly attaching thespines to the inflatable member in regions 1312″ may allow for moremovement and flexibility in the more flexible regions 1312″, which mayprovide more flexibility overall in the region of the scaffold, whichcan help when delivering the device. Any of the disclosure related toFIG. 13 may be incorporated by reference into any of the suitabledisclosure herein related to devices and methods of use that includesscaffolds that comprise both primary and secondary openings.

FIG. 13 also illustrates exemplary rail track or needle subassemblies1320′ and 1320″ within corresponding primary spines, which may include aplurality of needles and one or more fluid lumens, which are describedin more detail herein (there may be as many subassemblies as there arespines).

FIG. 13 also illustrates an exemplary proximal region of infusion device1300. The proximal region includes an adaptor 1339, which in thisexample is a three-port adaptor. Adaptor 1339 includes an inflation port1333 configured to couple to a fluid delivery device (e.g., InflationDevice commonly used with dilatation catheters) to deliver an inflationfluid to inflate expandable member 1350. Adaptor 1339 also houses aguidewire lumen 1341 therein, which is sized and configured to receiveguidewire 1337 therein, which may facilitate delivery of any of theinfusion devices herein over a guidewire. Adaptor 1339 also includes anactuator coupling region 1335, which may be sized and configured tocouple to an actuation member, an example of which is described in moredetail with respect to FIG. 14 .

Any other feature from any other infusion devices herein may beincorporated into the example in FIG. 13 , and vice versa.

FIG. 14 illustrates an exemplary proximal region of an infusion device,any features of which may be incorporated into any of the infusiondevices herein, including those with scaffolds that include primary andsecondary openings. The proximal region includes optionally three-portadaptor 1439, which may house a guidewire lumen 1441 therein that isadapted to receive a guidewire 1437 therein for guidewire delivery. Inthis example, the proximal handle region includes an actuator 1482 thatis in operational communication with the rail track subassemblies tofacilitate axial movement thereof, which are generally labeled 1420, butit is understand there may be two or more (such as the three that areshown). The rail track sub-assemblies 1420 may have proximal ends thatare attached (directly or indirectly) to an inner surface of actuator1482, such as by using any suitable bonding technique, which therebycauses the rail track subassemblies to move distally upon distalactuation of the actuator 1482, to thereby deploy the needles from thespine openings. In this example, actuator 1482 has a plunger typeconstruction, with a distal member 1484 that is sized to interface withinner surface 1486 to stop further movement of the actuator 1482. Thisstop mechanism is an example of a stop mechanism that is adapted tocontrol the distal travel of the actuator 1482. This can be set at anydesired distance to control the amount of needle deployment. Theproximal portion also includes infusion port 1435, which is adapted tobe coupled to a source of therapeutic agent to facilitate deliverythereof through the one or more delivery lumens and to the needles. Aproximal region of an exemplary spine 1412 is also shown in FIG. 14 ,but it is understood that there may be as many spines as there are railtrack sub-assemblies. Any other feature from any other infusion devicesherein may be incorporated into the example in FIG. 14 , and vice versa.

FIGS. 15A and 15B are proximal end views of the proximal regionillustrated in FIG. 14 , including three-port adaptor 1539, with FIG.15B highlighting proximal ends of rails 1523 and fluid delivery lumens1522 housed therein. FIG. 15A illustrates inflation port 1533 generally,guidewire lumen 1541 generally, and proximal ends of rails 1523 andfluid delivery lumens 1522 therein. FIG. 15B focuses on exemplary rails1523′, 1523″, and 1523′. In this example each rail 1523 houses thereinthree fluid delivery lumens, 1522′, 1522″, and 1522′″, respectively. Thefluid delivery lumens are in fluid communication with the needles, suchthat a therapeutic agent may be delivered into the proximal ends of thefluid lumens 1522 and to the needles. Any other feature from any otherinfusion devices herein may be incorporated into the example in FIGS.15A and 15B, and vice versa.

Any of the needles may be deployable using an external component (thatremains outside the patient) that is operatively coupled to one or moreneedles of the infusion device.

In some exemplary embodiments, all of the needles in the infusion deviceare deployable in unison, and may be operatively coupled to a commondeployment actuator, an example of which is shown in FIG. 14 anddescribed above. It is understood that other mechanisms may be used todeploy the needles, either in unison or not in unison. For example, theexternal portion (which may be referred to herein as a proximal regionof the infusion device) may have more than one actuator, each of whichmay control a subsection of the plurality of needles.

Any of the needles herein may be referred to as microneedles, and may becomprised of nitinol, stainless steel, and/or a combination of nitinol,stainless steel, and other materials that adapt the needle to be ablepenetrate into the vessel wall. Any of the needles herein may range inlength from 0.1 mm-3 mm and in size from 20 gauge to 38 gauge, forexample. For clarity, the lengths and/or size of individual needles mayvary relative to any adjacent needles, either in the same spine ordifferent spines. Furthermore, the relative inner diameter, outerdiameter, and wall thickness of the individual needles may be uniformrelative to adjacent needles, or they may vary relative to any adjacentneedles, either in the same spine or different spines. Additionally, anyof the needles herein may have at least one of an inner diameter (“ID”)and an outer diameter (“OD”) that varies along the length of the needle.

Any of the expandable infusion scaffolds herein may be configured to bean integral part of the balloon system. Alternatively, any of theexpandable scaffolds herein may be configured as an independentstructure that works ‘in synergy’ with a balloon-based system but is notattached to the balloon system and is not integral to such. As isdescribed elsewhere herein, and incorporated into these embodiments, theexpandable scaffold may take the form of various potentialconfigurations designed to enable infusion lumen structural support andcommunication with the microneedles while also facilitatingcircumferential and longitudinal infusion of the intended agent to thetarget lesion.

In any of the infusion devices herein, the expandable infusion scaffoldmay comprise one or more infusion lumens extending in a longitudinal(axial direction; proximal-distal) or non-longitudinal pattern along atleast a portion of the length of the balloon that is either integral to,or to be used in synergy with the infusion scaffold. Longitudinal inthis context refers generally to at least a portion of an infusion lumenthat is parallel with a longitudinal axis of inflatable balloon. In someembodiments, the scaffold may comprise one or more infusion lumensextending in a non-longitudinal pattern along at least a portion of thelength of the balloon that is either integral to, or to be used insynergy with the infusion scaffold. Any of the infusion lumens hereinmay have one or more portions that extend longitudinally and one or moreportions that extend non-longitudinally. Examples of a non-longitudinalconfiguration or pattern in this context include a spiral or helicalconfiguration or other non-longitudinal pattern. For the sake ofillustration, the following describes infusion lumens that run or extendlongitudinally (axially) along at least a portion of the length of thescaffold. “Longitudinally” (and derivative thereof) and “axially” (andderivatives thereof) are generally used synonymously herein. “Linear”may also be used with longitudinal and axial when made in reference to alinear longitudinal or linear axial configuration, such as if parallelto a longitudinal (or long) axis of the infusion device or an inflatablemember.

In some exemplary embodiments herein (such as in FIG. 6A-6F), themicroneedles are secured (e.g., directly attached, or attached via oneor more intermediate components) to a rail or other elongate member thatis loaded into and disposed in the primary infusion spine. Exemplarybenefits of this design include, but are not limited to, 1) protectionof the balloon, guide catheter, delivery sheath, vessel wall, or anyother structure in proximity to the microneedles by isolating the sharpneedle points during delivery to the lesion site and/or removal from thelesion site; 2) the ability to use the scaffold to facilitate controlleddilation and optionally micro-penetration of the vessel wall ahead ofdeploying the infusion needles; and/or 3) added structural supportduring deployment of the needles. Needles that are secured to tracks orother elongate members herein may also enable the depth of needledeployment to be controlled or adjusted. For example, any of the railsherein may be in operable communication with an external portion (e.g.,as shown in FIG. 13-15B), wherein one or more actuators (e.g., rotatableknobs, axially movable sliders) in the external portion may be adaptedto be actuated to control the relative degree of motion of the railtrack subassembly (e.g., axial translation), and thereby control thelength of the needles that exit radially or somewhat radially outwardfrom the infusion spine.

Any of the microneedles herein may also have one or more side holes orports formed therein in addition to or alternatively to a port at adistal end of the needle. In variations of any of the embodimentsherein, the needles may only have side holes and may not have a distalhole. Side ports or holes may enable concurrent infusion at more thanone depth within the vessel wall. Exemplary benefits of having one ormore side holes in the needle include, but are not limited to, enablinglocal delivery of the therapeutic agent or diagnostic agent into themedial layer of the vessel as well as deep into the adventitial layer ofthe vessel.

Any of the rails herein may also be referred to as a support shaft, anyof which may be solid or have a lumen therein. The rails herein may bemade of any number of potential materials such as nitinol or stainlesssteel onto which the needles can be bonded or attached (directly orindirectly), and which may optionally be slatted or laser cut along atleast a portion thereof to provide enhanced trackability. Additionally,any of the rails herein may be comprised of more than one type ofmaterial along the length of the device. Any of the individual needlesherein may include a first end that may be straight or linear and theother free end may be pre-formed (e.g., heat set) to take aperpendicular or near perpendicular configuration (e.g. 60-120 degrees)to the surface of the vessel when the needle is in its deployed state. Astraight or linear section of a needle may be individually secured(e.g., directly attached) to an axially moveable member such as a rail,allowing the free end to be free to deform and assume its deployed shape(e.g., pre-set shape) as it exits the infusion spine opening.

Axial spacing between needles may be optimized based on the desiredanatomical coverage of the agent within the vessel wall, along withspacing to facilitate optimal delivery and trackability of the infusiondevice to the target lesion.

In any of the embodiments herein, any number of distal ends ofindividual infusion spines (primary and optional secondary) may beaxially staggered (or axially offset, or spaced axially) relative to anyother infusion spine distal ends, further enhancing trackability of thedistal end region of the device (an example of which is in FIG. 1 ). Inany of the embodiments herein, at least two lumens may have distal endsthat are axially aligned, but those distal ends may be axially spacedfrom one or more other infusion lumen distal ends. In this fashion, anynumber of infusion lumen distal ends may be axially aligned or axiallystaggered relative to any number of other infusion lumen distal ends. Inthe exemplary embodiment shown in FIG. 1 , the infusion lumens arecircumferentially staggered or off-set around or about the scaffold andinflatable member, as well as having distal ends that are axially offsetsuch that the corresponding infusion needles are offset. In theexemplary embodiment shown in FIG. 5 , the infusion lumens arecircumferentially staggered or off-set around or about the scaffold andinflatable member, but axially aligned at the distal ends such that thecorresponding infusion needles are axially aligned.

As described elsewhere herein, the individual rail remains inside therespective primary infusion spine, serving as a mechanism by which toadvance and retract the microneedles. One or more openings (or windows)in the primary infusion spine provide guidance (or a pathway) for themicroneedle(s) to exit the infusion spine and can also be adapted tofunction as added structural support as the needle penetrates into thevessel wall. Any of the infusion spine windows or openings herein (whichmay also be described as “space,” and as such may be defined bysurrounding structure in the infusion spine, for example) may beconfigured with a slight tented structure around the perimeter thereofto offer additional guidance and structural support, or they may beconfigured to be flat or concave relative to the cross-section of theinfusion spine. The primary infusion spines herein may also beconfigured to have a structure located just distal or just proximal toan opening or window (the structure may define the surface(s) of the“opening”) that is configured to function as an additional intraluminalguide or ramp as the needle advances out of the infusion spine opening.

In any of the examples herein, advancement and retracting of one or morerails or support shafts, to which one or more microneedles are secured(directly or indirectly), may be enabled through a mechanical turn dial(or any other rotatable handle actuator) or any other mechanicalactuation mechanism with intuitive settings to guide the user duringdeployment and retraction of the microneedles.

In any of the examples herein, after the microneedles are deployed,infusion may be initiated using, for example only, a controlledmechanism of volume delivery based on the lesion length and desiredvolume of agent infused.

In any of the examples herein, the number of needles per primaryinfusion spine may be of any desired number, inclusive but not limitedto the range of two to fifty microneedles per primary infusion spine. Insome embodiments, the microneedles may be attached or otherwise securedby techniques such as welding, soldering, mechanical crimping, adhesive,or other techniques to a rail and/or fluid delivery lumen. The needlesherein may be bonded directly to a fluid delivery lumen, or they bebonded to one or more intermediate elements such as a coupler. Further,as is described in more details elsewhere herein, the depth of needledeployment may be controlled or adjusted, for example, by utilizing oneor more controls in an external portion of the device that may beadapted to control the relative degree of motion of the rail track orsupport shaft subassembly and thereby control the length of needle thatexits radially or somewhat radially outward from the device.

In some examples herein, each needle associated with a primary spine isin fluid communication with an individual and separate fluid deliverylumen along at least a portion of the catheter length.

Any of the fluid delivery lumens herein may have one of a variety ofcross-sectional shapes inclusive of, but not limited to, round andkidney shaped. This may be done to help reduce the overall profile ofthe needle assembly without compromising the volume of agent that can beinfused through the lumen(s). FIG. 10 is a sectional view through one ofthree needles associated with a particular spine (spine not shown forclarity). FIG. 10 shows exemplary rail 1023, exemplary needle 1014 andfluid delivery lumens 1022 and 1024 that are in fluid communication witha second and third needle, respectively, which are not shown as they areaxially spaced from needle 1014. For example only, needle 1014 may be aproximal needle with two additional needles distal to needle 1014. Inthis example, rail 1023 is mechanically crimped and has a non-circularouter profile as shown. Fluid delivery lumens 1022 and 1024 havenon-circular sectional shapes, which in this example can be approximatedto kidney shaped, and may be crescent shaped in other embodiments.Alternatively, FIG. 9 illustrates a cross section of a rail trackassembly 920 (920 is also pointing to the rail element) including needle914 a and fluid delivery lumens 922′ and 922″, wherein the cross sectionof the rail and the fluid delivery lumens are circular.

Any of the lumens herein may be comprised of one or more materialsinclusive of, but not limited to, polyimide, polymer, nitinol,composite, and/or combination thereof. Any of the fluid delivery lumensand needles within a rail may be secured using a variety of potentialtechniques such as, without limitation, crimping, welding, soldering,potting, adhesive, or other techniques inclusive of a combinationthereof. In any of these embodiments, any single needles may thus be influid communication with a unique or distinct fluid delivery lumen thatis only in fluid communication with that particular needle and not anyother needles. In alternatives, a plurality of needles may be in fluidcommunication with a first fluid delivery lumen, and a different needlemay be in fluid communication with a second fluid delivery lumen.

In any of the embodiments herein wherein the expandable scaffold isattached to the inflatable member, the scaffold and/or individual spinesmay be bonded to the balloon or secured between the balloon and anadditional thin walled layer of material, for example.

As disclosed elsewhere herein, in any of the embodiments herein, theinfusion scaffold may be independent from the expansion balloon (notintegrated therewith), yet is adapted to function in synergy with theexpansion balloon. In these embodiments, the scaffold may be deployedprior to inflation of the balloon. For example, upon retraction of anouter scaffold sheath, the scaffold may be adapted to be self-expanding,partially self-expanding, or non-self-expanding. The expansion balloonmay be then advanced within the scaffold and dilated to continue to orfully expand the infusion scaffold. The scaffold structure may bedeployed passively by retracting an outer sheath (as would aself-expanding stent) or by a mechanical means activated in the handleof the device. The infusion scaffolds herein may be compatible with anyoff-the-shelf angioplasty balloon, and the balloon may optionally bedrug-coated or uncoated. In some of these embodiments, the scaffold maybe pre-loaded onto the expansion balloon (yet not attached thereto),with both delivered to the target lesion in unison, and the infusionscaffold may then be expanded as the dilatation balloon is expanded. Thescaffolds herein may thus be at least partially deployed with anexpansion balloon, but need not be bonded thereto.

In alternative examples, the scaffolds herein may be independent withoutthe use of an expansion balloon. For example, the scaffold may bedeployed into a target vessel and expanded radially. Radial expansionmay be accomplished passively by retracting an outer sheath (as would aself-expanding stent that is commonly used in the field) and/or by amechanical mechanism activated in the handle of the device. In anexemplary embodiment, the infusion scaffold is configured and adapted tobe expanded using a mechanical mechanism or approach that compressesparts of the infusion scaffold longitudinally. The needles may then beadvanced, as is described in more detail herein.

In some methods of use, the expandable scaffolds herein may be deliveredabout an inflatable member, either attached to the balloon or not. Afterthe inflatable member and scaffold are delivered to the target locationwithin a vessel, an inflation can be delivered to an inner volume withinthe inflatable balloon to cause its expansion. This balloon expansionapplies a force to the expandable scaffold, causing the scaffold andspine to radially expand towards the vessel wall. The balloon can beexpanded until the infusion device makes contact with the vessel wall.The needles may then be deployed from the spine opening and into thevessel wall, which is described in more detail elsewhere herein, andoptionally by distally advancing one or more rails within the spines.The agent may then be delivered from a fluid source, through the one ormore fluid delivery lumens, and out of the one or more needle ports andinto the vessel wall optionally including the adventitia. The needlesmay be retracted by retracting one or more rails, and the scaffold andinflatable member may then be collapsed. The infusion device may then berecaptured (e.g., within a sheath or guide catheter) within a deliverysheath and removed from the patient or delivered to another location fora subsequent agent delivery process.

The disclosure that follows is also related to the disclosure aboverelated to intravascular devices adapted and configured for delivery ofa therapeutic and/or diagnostic agent into a wall of a target vessel ofa human patient. Any of the suitably combinable disclosure from abovemay be incorporated into the devices and methods that follow.

As set forth above, while the primary spines and associated needlesherein can be used to deliver a therapeutic agent relatively deep intothe vessel wall (e.g., into the adventitia), it may also be beneficialto deliver an agent to less depth, such as onto the inner surface orinto the intima of the vessel wall. The disclosure that followsfacilitates delivery of one or more agents to different depth and intodifferent layers of the vessel wall with the same device and withouthaving to move the device within the vessel.

In some embodiments, the device comprises a scaffold that includes bothprimary openings, from which needles are deployed, and secondaryopenings, from which a secondary agent is delivered without use of aneedle. The needles facilitate deeper delivery of a primary agent, whilethe secondary openings facilitate delivery of a secondary agent to theintima layer of the vessel wall. This facilitates two therapeuticapproaches to different regions of the vessel. In some exemplary uses,an anti-restenosis primary therapeutic agent may be delivered deeperwith the needles, while an anti-recoil secondary therapeutic agent, suchas one or more vasodilators, may be delivered to less depth to theintimal layer of the vessel. The secondary agent may be adapted to treatelastic recoil of the vessel (e.g., acute) in response to deploying thedevices herein into contact with the vessel wall. In some examples,needles may be used to deliver a primary agent deeper into the vesselwall for a first therapy, and a secondary agent may be delivered throughsecondary openings to a shallower location in the vessel wall to treat amore acute condition such as elastic recoil. Any of the primary agentsherein (which are delivered through needles) may be the same as thesecondary agent, or the primary agent may be different than thesecondary agent.

FIGS. 17A-17C illustrates a portion of exemplary intravascular apparatus1700, which is shown with balloon 1702 inflated in a cylindricalconfiguration, and the expandable scaffold is expanded. The expandableinfusion scaffold comprises one or more primary spines 1704′ and 1704″that are disposed about the outer cylindrical surface of the inflatableballoon, as shown. The primary spines include a plurality of primaryradial openings 1708 therethrough, each of the plurality of primaryradial openings 1708 associated with a needle 1720 that has a deliveryconfiguration (not shown in FIGS. 17A-17C) within the primary spinelumen 1730 of the primary spine (1704′ and 1704″) in which a distal tipof the needle is radially constrained by the primary spine, and adeployed configuration (as shown) in which the needle 1720 extendsradially outward from the associated primary opening 1708 after theneedle is advanced axially relative to the primary spine (1704′ and1704″).

The one or more primary spines (1704′ and 1704″) further comprise one ormore secondary openings 1706 therethrough that are not associated with aneedle and are not adapted to deploy a needle therefrom. The one or moresecondary openings 1706 are in communication with the primary spinelumen 1730 to facilitate delivery of a secondary agent 1710 from aproximal end of the apparatus, through the primary spine lumen 1730, andout of the one or more secondary openings 1706 into the intimal layer ofthe vessel wall.

Primary agent 1712 is shown being delivered from needles 1720, andsecondary agent 1710 is shown being delivered from the one or moresecondary openings 1706 as well as primary openings 1708. As shown inFIG. 17B, the primary agent 1712 is delivered through a fluid pathwaythat includes the needles 1720. As is also shown in FIG. 17B, secondaryagent 1710 is delivered through primary spine lumen 1730, which in thisembodiment is a space or volume between an inner surface of the spineand an outer surface of the needles.

As is described in more detail below, the secondary openings shown inFIG. 17B include some secondary openings that are both axially andcircumferentially offset from one or more other secondary openings. Someof the secondary openings are circumferentially aligned, as shown.

Additionally, the secondary openings shown in FIG. 17B include somesecondary openings that are axially offset from the primary opening1708, as shown, and some secondary openings that are axially alignedwith a primary opening. Some secondary openings shown in FIG. 17B arecircumferentially aligned with the primary openings, while somesecondary openings shown in FIG. 17B are circumferentially offset fromthe primary openings.

Any of the secondary openings 1706 may have the same relative positionsin any of the secondary spines herein, with the understanding that thesecondary spine would exclude any primary openings.

FIG. 17C illustrates an end view of device 1700 from FIGS. 17A and 17B,illustrating primary agent 1712 delivered from the needles 1720 and intothe medial and/or adventitial layer of the vessel wall. Secondary agent1710 is shown delivered through secondary openings 1706 (as well asthrough the primary openings) to expose the vessel wall to the secondaryagent and in this example into the intimal layer of the vessel wall. Asshown in FIG. 17B, secondary agent 1710 is delivered from primary spinelumen 1730 and through primary openings 1708, from which the needles areextending radially outward.

FIG. 18 illustrates a portion of exemplary intravascular apparatus 1800that may incorporate any relevant disclosure from apparatus 1700 shownin FIGS. 17A-17C, including methods of use. Apparatus 1800 includes arail 1840, examples of which are described elsewhere herein and areincorporated by reference herein to the disclosure of FIG. 18 . Needles1820 (shown deployed) are secured to rail 1840 such that they areadapted to be axially moved together relative to primary spine 1804. Theapparatus also includes fluid lumens 1842 and 1844 that are in fluidcommunication with an individual needle, as shown. Proximal regions ofthe fluid lumens 1842 and 1844 are secured to rail 1840 with securingmembers 1850, which also act as a fluid barrier and direct primary agent1812 from within rail lumen 1841 into the fluid lumens 1842 and 1844.Securing members 1850 may be any suitable material that is adapted tohold the fluid lumens in place and acts as a fluid barrier, such as,without limitation, a potting adhesive.

Secondary agent 1810 is delivered from a proximal end of the apparatus,through primary spine lumen 1830, and out of the one or more secondaryopenings 1806 to expose the vessel wall to the secondary agent. Whilenot labeled in FIG. 18 , secondary agent 1810 is also delivered out ofprimary openings 1808, from which needles 1820 extend radially (which isdescribed and shown with respect to FIGS. 17A-17C). The primary openings1808 are thus also in communication with fluid lumen 1830. In thisexample, primary spine fluid lumen 1830 is a space or volume at leastpartially defined by the inner surface of primary spine 1804 and anouter surface of rail 1840.

The primary spines herein may also include one or more secondaryopenings. FIGS. 19A-19D illustrate top views of merely exemplarypositions of secondary openings relative to exemplary radial primaryopenings. Any of the relative positions in FIGS. 19A-19D may beincorporated into any of the primary spines herein.

FIG. 19A illustrates a primary spine 1904, which includes a plurality ofprimary radial openings 1908, and a plurality of secondary openings1906, 1906′ and 1906″, all of which are optionally circumferentiallyaligned with the plurality of primary openings 1908, as shown. Secondaryopenings 1906′ are examples of a plurality of secondary openings thatare axially in between adjacent primary openings, as shown.

FIG. 19B illustrates exemplary primary spine 1914, which includesprimary radial openings 1918 and secondary openings 1916, all of whichin this example are circumferentially offset from primary openings 1918.Three of the secondary openings 1916 are shown circumferentially alignedwith each other, and the other three of the secondary openings 1916 arecircumferentially aligned with each other, as shown. Three pairs of thesecondary openings 1916 are also axially aligned, as shown.

FIG. 19C illustrates exemplary primary spine 1924, which includesprimary radial openings 1928 and secondary openings 1926′ and 1926″.Secondary openings 1926′ are circumferentially aligned with but axiallyoffset from primary openings 1928, as shown. Secondary openings 1926″are circumferentially and axially offset from primary openings 1928, asshown. The three groups of three secondary openings are shown toillustrate partial helical group configurations of at least threesecondary openings.

FIG. 19D illustrates exemplary primary spine 1934, which includes one ormore primary radial opening 1938 (only one shown) and secondary openings1936. Secondary openings 1936 are axially aligned with primary opening1938 and circumferentially offset from primary opening 1938.

Any of the descriptions of the secondary openings in FIGS. 19A-19D canequally apply to secondary openings in any of the secondary spinesherein, with the understanding that the primary openings in FIGS.19A-19D would not be present in the secondary spine.

In any of the embodiments herein, any or all of the primary openings maybe larger than one or all of the secondary openings, whether thosesecondary openings are in a primary spine or in an optional secondaryspine. FIG. 17B is an example where primary openings 1708 are largerthan secondary openings 1706. FIGS. 19A-19D is an example where theprimary openings are larger than all of the secondary openings. In anyof the embodiments, at least one of the one or more secondary openingsmay be the same size as at least one of the plurality of primaryopenings.

In any of the primary spines herein that include secondary openings, thenumber of secondary openings can be different than the number of primaryopenings, optionally greater than the number of primary openings. Forexample, the section of the device shown in FIG. 17B includes moresecondary openings than primary openings. In some embodiments, thenumber of secondary openings may be the same as the number of primaryopenings.

The disclosure above describes spines that may be laser cut to impartflexibility along their lengths, which can increase flexibility fordelivery. In some embodiments, the laser cuts in the spines may in factconstitute the one or more secondary openings in the spine, which allowsthe secondary agent to pass through the cut(s) and into the vessel wall.Laser cuts herein are examples of more generalized discontinuities inthe wall of the spine, where the discontinuity is a secondary openingthat facilitates weeping of the secondary agent therethrough.

Both primary and optional secondary spines may include one or morediscontinuities (e.g., one or more cuts therein) therein that aresecondary openings. FIG. 21 is a side view of spine 2104 (which could bea primary or secondary spine) illustrating a secondary opening 2106 inthe form of a laser cut helical pattern that facilitates delivery ofsecondary agent 2110 out of the spine 2104. In embodiments in which thespine has a laser cut pattern, part of the spine may be covered by amembrane to maintain fluid integrity, and the uncovered portion may actas the secondary opening. In these embodiments, the laser cut patternmay facilitate weeping of the secondary agent out of the secondaryopening. In embodiments that include a laser cut pattern, a single,uninterrupted cut around the spine (e.g., in a helical configuration)may define a single secondary opening.

The needles may be adapted to be in communication with a first agentsource outside the patient, and secondary openings may be adapted to bein communication with a second agent source outside the patient. Thefirst and second sources may be the same sources, or they may bedifferent sources. The different sources may contain therein the sameagent or different agents.

Any of the intravascular apparatus herein may also include secondaryspine, which are spines that include one or more secondary opening anddo not include openings from which a needle is deployed. FIG. 20illustrates a distal end of intravascular apparatus 2000 where balloon2002 is inflated to a cylindrical configuration and primary spine 2002and secondary spine 2004 are disposed about an outer cylindrical surfaceof the balloon 2002.

Primary spine 2002 includes primary openings 2006, each of which isassociated with a deployable needle as is described herein. Secondaryspine 2004 includes one or more secondary openings 2022, which may haveany of the relative positions described herein. In some alternatives,the one or more secondary openings 2020 may include a discontinuity inthe spine 2004, such as a laser cut gap in the spine, examples of whichare described herein.

FIG. 20 also illustrates optional secondary openings 2008 in primaryspine 2002, which may be any of the one or more secondary openingsherein. When optional secondary openings 2008 are not included in spine2002, apparatus 2000 is an example of an apparatus with at least oneprimary spine without any secondary openings, and with at least onesecondary spine.

One aspect of the disclosure herein is a method of intravascular fluiddelivery and treatment, comprising: advancing an intravascular apparatusto a target location within a vessel; inflating a balloon toward acylindrical configuration to cause one or more primary spines of anexpandable infusion scaffold to expand toward a vessel wall and bedisposed about an outer cylindrical surface of the balloon when theballoon is inflated, wherein the one or more primary spines include aplurality of radial primary openings and one or more secondary openings;moving a plurality of needles axially within the one or more primaryspines and deploying the plurality of needles out of the radial primaryopenings such that tips of each of the plurality of needles pierce intothe vessel wall; delivering a primary fluid agent out of the pluralityof needles and into the vessel wall; and delivering a secondary fluidagent through a primary spine lumen and out of the one or more secondaryopenings to expose the vessel wall to the secondary agent.

The delivering steps may comprise delivering the primary fluid agentdeeper into the vessel wall than the secondary fluid agent, such as intothe adventitia with the secondary fluid agent exposed to the surface ofthe vessel wall and optionally to the intima.

In some embodiments delivering the primary fluid agent can comprisesdelivering an anti-restenosis agent out of the plurality of needles andinto the vessel wall.

In some embodiments, delivering the secondary fluid agent can comprisedelivering an anti-recoil agent out of the one or more secondaryopenings to expose the vessel wall (for example, at least the intimallayer) to the anti-recoil agent.

In some embodiments, the primary fluid agent may be the same as thesecondary fluid agent.

The secondary and primary agents may be delivered at the same time, orat different times. In some uses, there may be some overlap in theirdeliveries, even if the deliveries are initiated at different times. Insome embodiments, the primary agent may comprise more than one agent(e.g., two or more different therapeutics), which may be deliveredsimultaneously (e.g., in combination) or separately at different times.

In some embodiments, delivering the secondary agent out of the one ormore secondary openings may be initiated before the plurality of needlesare deployed from the radial primary openings. In some embodiments,delivering the secondary agent out of the one or more secondary openingsmay be initiated at a time subsequent to when the plurality of needlesare deployed from the radial primary openings.

In some embodiments, delivering the secondary agent out of the one ormore secondary openings is initiated at a time prior to delivering theprimary fluid agent out of the plurality of needles.

In some embodiments, delivering the secondary agent out of the one ormore secondary openings occurs while the primary fluid agent is beingdelivered out of the plurality of needles.

In some embodiments, delivering the secondary agent out of the one ormore secondary openings is initiated at a time subsequent to deliveringthe primary fluid agent out of the plurality of needles.

In some embodiments, such as shown in FIG. 18 , delivering a secondaryfluid agent through a primary spine lumen comprises delivering thesecondary fluid agent between an inner surface of the primary spine andan outer surface of an axially moveable rail to which the plurality ofneedles is secured. The primary agent may be delivered through a lumenof the rail before it reaches the plurality of needles.

The primary and secondary fluid agents may optionally be disposed infirst and second fluid sources outside of the patient when in use and influid communication with the primary and secondary openings. The devicesherein may be placed into communication with one or more agent sourcesprior to the procedure, and thus do not necessarily need to be incommunication with the sources when packaged. This may allow one ofseveral different agents and/or types of agents to be delivered with thefluid delivery devices herein.

What is claimed is:
 1. An intravascular apparatus adapted for deliveryof a fluid, comprising: an inflatable balloon having an inflatedcylindrical configuration; and an expandable infusion scaffoldcomprising one or more primary spines disposed about an outercylindrical surface of the inflatable balloon, the one or more primaryspines comprising a plurality of primary radial openings therethrough,each of the plurality of primary radial openings associated with aneedle that has a delivery configuration within a primary spine lumen ofthe primary spine in which a distal tip of the needle is radiallyconstrained by the primary spine, and a deployed configuration in whichthe needle extends radially outward from the associated primary radialopening after the needle is advanced axially relative to the primaryspine to facilitate delivery of a primary agent from the needle, and theone or more primary spines further comprising one or more secondaryopenings therethrough that are not associated with a needle and are notadapted to deploy a needle therefrom, and wherein the one or moresecondary openings are in communication with the primary spine lumen tofacilitate delivery of a secondary agent through the primary spine lumenand out of the one or more secondary openings.
 2. The apparatus of claim1, wherein the inflatable balloon has a tapered proximal end and atapered distal end, and wherein the cylindrical configuration of theballoon is in between the tapered proximal and distal ends.
 3. Theapparatus of claim 2, wherein the one or more primary spines are alsodisposed about the tapered proximal end.
 4. The apparatus of claim 1,wherein at least one of the one or more secondary openings iscircumferentially aligned with the plurality of primary openings.
 5. Theapparatus of claim 1, wherein at least one of the one or more secondaryopenings in the associated primary spine is circumferentially offsetfrom the plurality of primary openings.
 6. The apparatus of claim 5,wherein each of the one or more secondary openings in the associatedprimary spine is circumferentially offset from the plurality of primaryopenings.
 7. The apparatus of claim 1, wherein a first subset of the oneor more secondary openings are circumferentially aligned with theplurality of primary openings, and a second subset of the one or moresecondary openings are circumferentially offset from the plurality ofprimary openings.
 8. The apparatus of claim 1, wherein at least one ofthe one or more secondary openings is axially offset from the pluralityof primary openings.
 9. The apparatus of claim 1, wherein at least oneof the one or more secondary openings is axially aligned with andcircumferentially offset from one of the plurality of primary openings.10. The apparatus of claim 1, wherein the primary radial openings arealso in communication with the primary spine lumen to facilitatedelivery of the secondary agent out of the one or more primary openings.11. The apparatus of claim 1, wherein each of the plurality of primaryopenings is larger than one or more of the secondary openings.
 12. Theapparatus of claim 11, wherein each of the plurality of primary openingsis larger than each of the secondary openings.
 13. The apparatus ofclaim 1, wherein at least one of the one or more secondary openings isthe same size as at least one of the plurality of primary openings. 14.The apparatus of claim 1, wherein the number of secondary openings isdifferent than the number of primary openings, optionally greater thanthe number of primary openings.
 15. The apparatus of claim 1, whereinthe number of secondary openings is the same as the number of primaryopenings.
 16. The apparatus of claim 1, wherein a plurality of secondaryopenings are disposed axially in between first and second axiallyadjacent primary openings.
 17. The apparatus of claim 1, wherein theplurality of needles that are associated with the primary spine areadapted to be axially moved together relative to the associated primaryspine.
 18. The apparatus of claim 17, wherein the plurality of needlesthat are associated with the primary spine are secured to a rail that iswithin the primary spine, and wherein axial movement of the rail withinthe primary spine causes axial movement and deployment of the pluralityof needles.
 19. The apparatus of claim 18, wherein an inner surface ofthe primary spine and an outer surface of the rail at least partiallydefine a secondary agent pathway through which the secondary agent isdelivered.
 20. The apparatus of claim 1, wherein the plurality ofneedles are adapted to be in communication with a first therapeuticagent source, and wherein the plurality of secondary openings areadapted to be in communication with a second therapeutic agent source.21. The apparatus of claim 20, wherein the first and second sourceinclude therein the same agent or different agents.
 22. The apparatus ofclaim 1, wherein the plurality of needles and the plurality of secondaryopenings are adapted to be in communication with the same agent source.23. The apparatus of claim 1, wherein the one or more secondary openingscomprises one or more discontinuities in a wall of the primary spine inthe region of the primary spine that is disposed about the outercylindrical surface of the balloon when inflated, wherein the one ormore discontinuities are in communication with the primary spine lumento facilitate delivery of the secondary agent through the one or morediscontinuities in the primary spine.
 24. The apparatus of claim 23,wherein the one or more discontinuities in the wall of the primary spinecomprise one or more laser-cut sections of the primary spine tofacilitate delivery of the secondary agent through the laser cutsections of the primary spine when the secondary agent is delivered intoand through the primary spine lumen.
 25. The apparatus of claim 24,wherein the primary spine further comprises one or more discontinuitiesin the wall of the primary spine in a region of the primary spine thatis proximal to the region that is disposed about the outer cylindricalsurface of the balloon when inflated.
 26. The apparatus of claim 1,wherein the expandable infusion scaffold further comprises one or moresecondary spines that are disposed about the outer cylindrical surfaceof the inflatable balloon, wherein the secondary spines each compriseone or more secondary openings therethrough that are not associated witha needle and are not adapted to deploy a needle therefrom, wherein theone or more secondary openings of the associated secondary spine are incommunication with a secondary spine lumen to facilitate delivery of thesecondary agent through the secondary spine lumen and out of the one ormore secondary openings of the secondary spine.
 27. The apparatus ofclaim 26, wherein the inflatable balloon has a tapered proximal end anda tapered distal end, and wherein the cylindrical configuration is inbetween the tapered proximal and distal ends, and wherein the one ormore secondary spines are also disposed about the tapered proximal end.28. The apparatus of claim 26, wherein the one or more secondary spinesare arranged helically about the cylindrical surface of the inflatableballoon.
 29. The apparatus of claim 26, wherein the one or moresecondary spines are arranged axially about the cylindrical surface ofthe inflatable balloon.
 30. The apparatus of claim 26, wherein at leasttwo or more secondary openings of the secondary spine arecircumferentially aligned.
 31. The apparatus of claim 26, wherein atleast two or more secondary openings of the secondary spine arecircumferentially offset.
 32. The apparatus of claim 26, wherein atleast two or more secondary openings of the secondary spine are axiallyoffset.
 33. The apparatus of claim 26, wherein at least two or moresecondary openings of the secondary spine are axially aligned.
 34. Theapparatus of claim 26, wherein a subset of the one or more secondaryopenings are arranged in an at least partial helical configuration. 35.The apparatus of claim 26, wherein the one or more secondary openings inthe secondary spine comprises one or more discontinuities in a wall ofthe secondary spine in the region of the secondary spine that isdisposed about the outer cylindrical surface of the balloon wheninflated, wherein the one or more discontinuities are in communicationwith the secondary spine lumen to facilitate delivery of the secondaryagent through the one or more discontinuities in the secondary spine.36. The apparatus of claim 35, wherein the one or more discontinuitiesin the wall of the secondary spine comprise one or more laser-cutsections of the secondary spine to facilitate delivery of the secondaryagent through the laser cut sections of the secondary spine when thesecondary agent is delivered into and through the secondary spine lumen.37. The apparatus of claim 35, wherein the secondary spine furthercomprises one or more discontinuities in the wall of the secondary spinein a region of the secondary spine that is proximal to the region thatis disposed about the outer cylindrical surface of the balloon wheninflated.
 38. The apparatus of claim 1, wherein the one or more primaryspines are arranged helically about the cylindrical surface of theinflatable balloon.
 39. The apparatus of claim 1, wherein the one ormore primary spines are arranged axially about the cylindrical surfaceof the inflatable balloon.
 40. The apparatus of claim 1, where aplurality of needles associated with each of the one or more primaryspines are operatively coupled such that they are adapted to be movedaxially as a group relative to the associated primary spine.
 41. Theapparatus of claim 40, wherein the plurality of needles are operativelycoupled to an axially moveable rail that is disposed within theassociated primary spine lumen such that the rail and the plurality ofneedles are adapted to be moved axially together.
 42. The apparatus ofclaim 41, wherein the rail comprises a rail lumen that is in fluidcommunication with the plurality of needles.
 43. The apparatus of claim42, wherein each of the plurality of needles is in fluid communicationwith a distinct fluid delivery lumen that is also in fluid communicationwith the rail lumen.
 44. The apparatus of claim 41, wherein the railincludes a plurality of radially outwardly disposed openings, each ofthe plurality of needles disposed at a location of one of the pluralityof radially outwardly disposed openings.
 45. The apparatus of claim 1,wherein the one or more primary spines extend along at least half of thelength of the portion of the balloon that has the inflated cylindricalconfiguration.
 46. The apparatus of claim 1, wherein a portion of theballoon that has the inflated cylindrical configuration has a lengthfrom 20 mm to 200 mm.
 47. The apparatus of claim 1, wherein theexpandable infusion scaffold is attached to the inflatable balloon alongat least a portion of a length of the scaffold.
 48. The apparatus ofclaim 1, wherein the expandable infusion scaffold is not attached to theinflatable balloon.
 49. The apparatus of claim 1, wherein the one ormore primary spines each have a stiffness that is not constant along thelength of the inflatable member.
 50. The apparatus of claim 1, whereinthe plurality of needles are operatively coupled to an axially moveablerail that is disposed within the associated primary spine lumen, andwherein the rail has a stiffness that is not constant along theinflatable balloon.
 51. The apparatus of claim 1, wherein the one ormore primary spines comprise one or more of nitinol, stainless steel,polymer, polyimide, or a braided member.